Building a Systems-Level View of Cell Cycle Checkpoints

因为细胞周期是所有真核生物生长和发育的基础，也是细胞调控失调的基础 周期代表癌症，实现了对细胞周期如何控制的系统水平的理解 现代细胞生物学中最重要的目标之一。将实验生物学与数学相结合 在高度交互的协作中进行建模创建了一种强大的方法来开发全面的 对细胞周期控制的理解。这一方法被用来发现有丝分裂转换是受调控的 通过磁滞和双稳态。下一个目标是通过解决一个关键问题来建立这个基础：如何 细胞周期引擎受到外部事件的影响，特别是那些威胁到 基因组。当对基因组稳定性构成威胁时，检查点停止细胞周期，例如未复制或 存在损坏的DMA。几乎所有的癌细胞都会失去对检查点的控制。检查点将是 研究了实验上易处理的非洲爪哇卵和非洲爪哇卵的无细胞提取物 非洲爪哇胚胎，细胞周期在早期发育期间广泛重塑。为了建造这个 理解，将构建DNA复制检查点的数学模型并对其进行 严格的实验测试。该模型应该揭示潜在的动态控制，并充当 预测病理和药物扰动对细胞周期影响的有力工具 检查站。为了实现构建DNA复制检查点的系统级视图的目标， 将完成以下具体目标：1)表示未复制的影响的数学模型 将构建核心细胞周期引擎上的DNA，优化参数，并将模型 在万维网上供公众使用。2)同时，关键的定量实验 关于细胞核浓度和细胞周期酶如何影响DNA复制检查点 进行的数据和用于通知模型的数据。3)一旦这种关于未复制DNA的基本观点 影响细胞周期引擎已在手中，该模型将扩展到包括Chk1激酶信号 途径，癌症化疗药物的关键潜在靶点。4)最后，该模型将受到挑战 准确地表示了DNA复制检查点在早期发育过程中的三种不同行为， 为模型提供生理测试用例，并通知哪里需要额外数据。

Because the cell cycle underlies the growth and development of all eukaryotes, and misregulation of the cell cycle typifies cancers, achieving a systems-level understanding of how the cell cycle is controlled ranks among the most important goals in modern cell biology. Pairing experimental biology with mathematical modeling in a highly interactive collaboration creates a powerful approach to develop a comprehensive understanding of cell cycle control. This approach was used to discover that mitotic transitions are regulated by hysteresis and bistability. The next goal is to build on this foundation by addressing a critical issue: how the cell cycle engine is affected by external events, in particular, those events that threaten the integrity of the genome. Checkpoints arrest the cell cycle when a threat to genomic stability, such as unreplicated or damaged DMA, exists. Loss of checkpoint control characterizes nearly all cancer cells. Checkpoints will be investigated in the experimentally tractable cell-free extracts derived from eggs of Xenopus laevis and in Xenopus embryos, where the cell cycle extensively remodels during early development. To build this understanding, a mathematical model of the DNA replication checkpoint will be constructed and subjected to rigorous experimental testing. This model should reveal underlying dynamical controls and serve as a powerful tool for predicting the effect of pathologic and pharmacologic perturbations upon cell cycle checkpoints. To reach the goal of constructing a systems-level view of the DNA replication checkpoint, the following specific aims will be completed: 1) A mathematical model representing the effect of unreplicated DNA on the core cell cycle engine will be constructed, parameters will be optimized, and the model will be made available for public use on the World Wide Web. 2) Concurrently, key quantitative experiments concerning how nuclear concentration and cell cycle enzymes impact the DNA replication checkpoint will be conducted and data used to inform the model. 3) Once this fundamental view of how unreplicated DNA affects the cell cycle engine is in hand, the model will be extended to include the Chk1 kinase signaling pathway, a key potential target for cancer chemotherapeutics. 4) Finally, the model will be challenged to accurately represent three distinct behaviors of the DNA replication checkpoint during early development, providing a physiologic test case for the model and informing where additional data are needed.